US7888329B2ExpiredUtilityPatentIndex 84
Substituted aryl piperidinylalkynyladenosines as A2AR agonists
Est. expiryMay 18, 2026(expired)· nominal 20-yr term from priority
A61P 9/00A61P 37/06A61P 37/02A61P 37/00A61P 37/08A61P 9/10A61P 43/00A61P 31/00A61P 29/00A61P 13/12A61P 11/00A61P 17/00C07H 19/19A61P 17/02
84
PatentIndex Score
12
Cited by
5
References
21
Claims
Abstract
A 2A agonists of formula (I) is provided, wherein R 1 , R 2 , R 4 , R 5 , X, Y, Z, n, p, and q are as described herein. Also provided are compositions comprising and methods of using compounds of formula (I).
Claims
exact text as granted — not AI-modified1. A method for treating a pathological condition or symptom in a subject, wherein the activity of A 2A adenosine receptors is implicated and agonism of such activity is desired, comprising administering to the subject an effective amount of a compound of formula Ia or a pharmaceutically acceptable salt thereof:
R 1 and R 2 independently are selected from the group consisting of H, (C 1 -C 8 )alky, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkylene, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, diaryl(C 1 -C 8 )alkylene, and diheteroaryl(C 1 -C 8 )alkylene, wherein the aryl and heteroaryl rings are optionally substituted with 1-4 groups independently selected from fluoro, chloro, iodo, bromo, methyl, trifluoromethyl, and methoxy;
each R independently is selected from the group consisting of H, C 1 -C 4 alkyl, cyclopropyl, cyclobutyl, and (CH 2 ) a cyclopropyl;
X is CH or N, provided that when X is CH then Z cannot be substituted with halogen, C 1 -C 6 alkyl, hydroxyl, amino, or mono- or di-(C 1 -C 6 -alkyl)amino;
Y is selected from the group consisting of O, NR 1 ,—(OCH 2 CH 2 O) m CH 2 —, and —(NR 1 CH 2 CH 2 O) m CH 2 —, provided that when Y is O or NR 1 , then at least one substituent is present on Z;
Z is selected from the group consisting of 5-membered heteroaryl, 6-membered aryl, 6-membered heteroaryl, carbocyclic biaryl, and heterocyclic biaryl, wherein the point of attachment of Y to Z is a carbon atom on Z, wherein Z is substituted with 0-4 groups independently selected from the group consisting of F, Cl, Br, I, (C 1 -C 4 )alkyl, —(CH 2 ) a OR 3 , —(CH 2 ) a NR 3 R 3 ,—NHOH, —NR 3 NR 3 , nitro, —(CH 2 ) a CN, —(CH 2 ) a CO 2 R 3 , —(CH 2 ) a CONR 3 R 3 ,trifluoromethyl, and trifluoromethoxy;
alternatively, Y and Z together form an indolyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, or tetrahydroquinolinyl moiety wherein the point of attachment is via the ring nitrogen and wherein said indolyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, or tetrahydroquinolinyl moiety, which is substituted with 0-4 groups independently selected from the group consisting of F, Cl, Br, I, C 1 -C 4 alkyl, —(CH 2 ) a OR 3 , —(CH 2 ) a NR 3 R 3 , —NHOH, —NR 3 NR 3 R 3 , NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R 3 , —(Ch 2 ) a CONR 3 R 3 , CF 3 , and OCF 3 ;
R 3 is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, cycloalkyl, aryl, and heteroaryl;
R 4 is selected from the group consisting of CH 2 OR, C(O)NRR, and CO 2 R;
a is selected from 0, 1, and 2;
m is selected from 1, 2, and 3;
n is selected from 0, 1, and 2;
each p independently is selected from 0, 1, and 2; and,
q is selected from 0, 1, and 2.
2. The method of claim 1 , wherein the pathological condition or symptom is caused by autoimmune stimulation (autoimmune diseases), inflammation, allergic diseases, skin diseases, infectious diseases, wasting diseases, organ transplantation, tissue or cell transplantation, open wounds, adverse effects from drug therapy, a cardiovascular condition, ischemia-reperfusion injury, dialysis, gout, chemical trauma, thermal trauma, diabetic nephropathy, sickle cell disease, laminitis, and founder's disease.
3. A method to diagnose myocardial perfusion abnormalities in a mammal comprising: (a) parenterally administering to said mammal an amount of a compound of formula Ia or a pharmaceutically acceptable salt thereof: and (b) performing a technique on said mammal to detect the presence of coronary artery stenoses, assess the severity of coronary artery stenoses or both
R 1 and R 2 independently are selected from the group consisting of H, (C 1 -C 8 )alky, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkylene, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, diaryl(C 1 -C 8 )alkylene, and diheteroaryl(C 1 -C 8 )alkylene, wherein the aryl and heteroaryl rings are optionally substituted with 1-4 groups independently selected from fluoro, chloro, iodo, bromo, methyl, trifluoromethyl, and methoxy;
each R independently is selected from the group consisting of H, C 1 -C 4 alkyl, cyclopropyl, cyclobutyl, and (CH 2 ) a cyclopropyl;
X is CH or N, provided that when X is CH then Z cannot be substituted with halogen, C 1 -C 6 alkyl, hydroxyl, amino, or mono- or di-(C 1 -C 6 -alkyl)amino;
Y is selected from the group consisting of O, NR 1 ,—(OCH 2 CH 2 O) m CH 2 —, and —(NR 1 CH 2 CH 2 O) m CH 2 —, provided that when Y is O or NR 1 , then at least one substituent is present on Z;
Z is selected from the group consisting of 5-membered heteroaryl, 6-membered aryl, 6-membered heteroaryl, carbocyclic biaryl, and heterocyclic biaryl, wherein the point of attachment of Y to Z is a carbon atom on Z, wherein Z is substituted with 0-4 groups independently selected from the group consisting of F, Cl, Br, I, (C 1 -C 4 )alkyl, —(CH 2 ) a OR 3 , —(CH 2 ) a NR 3 R 3 , —NHOH, —NR 3 NR 3 R 3 , nitro, —(CH 2 ) a CN, —(CH 2 ) a CO 2 R 3 , —(CH 2 ) a CONR 3 R 3 ,trifluoromethyl, and trifluoromethoxy;
alternatively, Y and Z together form an indolyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, or tetrahydroquinolinyl moiety wherein the point of attachment is via the ring nitrogen and wherein said indolyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, or tetrahydroquinolinyl moiety, which is substituted with 0-4 groups independently selected from the group consisting of F, Cl, Br, I, C 1 -C 4 alkyl, —(CH 2 ) a OR 3 , —(CH 2 ) a NR 3 R 3 , —NHOH, —NR 3 NR 3 R 3 , NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R 3 , —(Ch 2 ) a CONR 3 R 3 , CF 3 , and OCF 3 ;
R 3 is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, cycloalkyl, aryl, and heteroaryl;
R 4 is selected from the group consisting of CH 2 OR, C(O)NRR, and CO 2 R;
a is selected from 0, 1, and 2;
m is selected from 1, 2, and 3;
n is selected from 0, 1, and 2;
each p independently is selected from 0, 1, and 2; and,
q is selected from 0, 1, and 2.
4. The method of claim 1 , wherein the compound is of formula (Ib) or a pharmaceutically acceptable salt thereof:
wherein:
each Z′ is independently selected from the group consisting F, Cl, Br, I, C 1 -C 4 alkyl, —(CH 2 ) a OR 3 , —(CH 2 ) a NR 3 R 3 , —NHOH, —NR 3 NR 3 R 3 , NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R 3 , —(CH 2 ) a CONR 3 R 3 , CF 3 , and OCF 3 .
5. The method of claim 4 , wherein R is selected from H, methyl, ethyl or cyclopropyl.
6. The method of claim 4 , wherein the compound is of formula (Ic) or a pharmaceutically acceptable salt thereof:
7. The method of claim 6 , wherein Z′ is selected from the group consisting of F, Cl, methyl, OR 3 , NO 2 , CN, NR 3 R 3 and CO 2 R 3 .
8. The method of claim 6 , wherein R 3 is methyl or hydrogen.
9. The method of claim 1 , wherein the compound is selected from the group consisting of Compound Numbers 3, 5-31, and 33-57 shown in Table 1 below:
R 4 =A: CH 2 OH; B: C(O)NEthyl; C: C(O)NCyclopropyl;
Compounds are of formula (i), unless indicated:
Human
Human
Human
Compound
A 1
A 2A
A 3
Functional
Number
R 4
Z′
(nM)
(nM)
(nM)
(nM)
3
C
++
++++
++
+++
5
C
++
++++
++
+++
6
A
++
++++
+++
+++
7
A
++
++++
++
+++
8
C
++
++++
++
++++
9
C
++
++++
++
+++
10
C
++
++++
++
++++
11
A
++
++++
++
+++
12
A
++
++++
++
++++
13
A
++
++++
++
+++
14
C
+
+++
+
++
15
B
++
++++
+++
++++
16
B
++
++++
+++
++++
17
C
++
++++
++
++++
18
C
++
++++
++
++++
19
B
++
++++
+++
++++
20
C
++
++++
+
++++
21
C
++
++++
++
+++
22
C
++
++++
+
+++
23
C
++
++++
++
++++
24
B
++
++++
+++
++++
25
B
+
+++
++
+++
26
B
++
++++
+++
++++
27
A
++
++++
++
+++
28
A
++
++++
++
+++
29
A
++
++++
++
+++
30
A
++
+++
++
+++
31
B
++
++++
+++
+++
33
B
++
++++
+++
+++
34
B
++
+++
++
++++
35
A
++
++++
++
+++
36
A
++
++++
++
+++
37 (iii)
B
++
++++
++
+++
38 (iii)
C
+
++
+
++
39 (iii)
C
+
++
+
++
40 (iii)
C
+
+++
+
++
41 (iii)
C
++
+++
+
+++
42
C
+
+++
+
+
43 (ii)
C
++
+++
+
++
44 (ii)
A
++
+++
++
+
45 (ii)
A
++
+++
++
+
46 (ii)
A
++
+++
++
++
47 (ii)
C
++
++++
++
++++
48 (ii)
C
+
+++
+
+++
49
B
++
++++
+++
++++
50
B
++
++++
++
++++
51
C
++
++++
++
++++
52
C
++
++++
++
++++
53
A
++
++++
++
+++
54
A
++
++++
++
+++
55
A
++
++++
+++
+++
56
C
++
++++
+
++++
57
C
++
++++
++
+++
Legend for Compound Activity
++++ <1.0 nM
+++ <10 nM
++ <100 nM
+ >100 nM
• Indicates Point of Attachment of Z group to Y.
10. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
11. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.Cited by (0)
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